Serotonin and the catecholamines are known to play a role in the regulation of blood pressure. Serotonin agonists, alpha-2 receptor agonists and dopamine agonists have all been shown to lower blood in hypertensive animals. Humans with hypertension are routinely treated with clonidine and alpha methyldopa, two drugs which lower blood pressure by central stimulation of alpha-2 adrenoreceptors. Despite the therapeutic success of these drugs, there is no detailed knowledge of how individual brainstem nuclei use norepinephrine, epinephrine, dopamine and serotonin during changes in blood pressure. With the new technique of in vivo electrochemistry, we have been able to follow the time course of catechol and 5-HIAA concentrations continuously during drug- induced hypertension and hypotension. During the first award period of this grant, we found that the serotonin metabolite 5- HIAA was increased in most nuclei whenever blood pressure was increased. The catechol peak was generally reduced during hypertension. We found that only in the C1 nucleus were the electrochemical peaks for catechols and indoles reciprocally related to blood pressure for both hypertension and hypotension. In preliminary experiments, we have also found that the catechol peak in the lateral hypothalamus is inversely and linearly related to serum osmolarity. In the renewal of this grant we will study catechol and indole metabolism in nucleus tractus solitarius, locus coeruleus, the C1 and A1 areas, the nucleus ambiguous, the paraventricular nucleus, the preoptic area and lateral hypothalamus during changes in serum osmolarity and circulating volume. In addition to in vivo electrochemistry, we will use in vivo dialysis to study norepinephrine and epinephrine release in C1 nucleus during drug induced changes in blood pressure. Effects of osmotic changes will be compared in Sprague Dawley and vasopressin deficient Brattleboro rats. The ability of vasopressin to reset baroreceptor gain and lower catechols in NTS will be compared with the effect of vasopressin infusions on catechol and indole release in other brainstem nuclei. These experiments should characterize the role of monoamines in individual brainstem nuclei in maintaining blood pressure, serum osmolarity, and circulating volume. Results of these studies already suggest a new therapy for hypertension. Serotonin agonists and alpha-2 agonists may make a potent antihypertensive combination.